阅读说明：本技术 一种高纯度盐酸艾司洛尔的制备工艺 (Preparation process of high-purity esmolol hydrochloride ) 是由 潘继成 金晓民 杨建荣 臧月龙 沈佳 张楠 沈志佳 于 2021-07-16 设计创作，主要内容包括：本发明属于有机化学和医药化工技术领域,尤其涉及一种高纯度盐酸艾司洛尔的制备工艺。本发明的目的是提供一种高纯度盐酸艾司洛尔的制备工艺,其能通过先将对羟苯丙酸与甲醇,在第一催化剂的作用下,进行酯化反应,得到对羟苯丙酸甲酯,再将所述对羟苯丙酸甲酯与环氧氯丙烷,在第二催化剂的作用下反应,得到3-［4-(2,3-环氧丙氧基)苯基］丙酸甲酯接着在甲醇溶剂中,依次加入将所述3-［4-(2,3-环氧丙氧基)苯基］丙酸甲酯、异丙胺以及氯化氢,反应后得到粗盐酸艾司洛尔,最后对所述粗盐酸艾司洛尔依次进行加热溶解、活性炭脱色、冷却析晶、离心以及干燥操作的方式,得到总杂低于0.5%,单个未知单杂低于0.05%的最终的高纯度盐酸艾司洛尔。(The invention belongs to the technical field of organic chemistry and pharmaceutical chemistry, and particularly relates to a preparation process of high-purity esmolol hydrochloride. The invention aims to provide a preparation process of high-purity esmolol hydrochloride, which comprises the steps of firstly mixing p-hydroxyphenylpropionic acid and methanol, carrying out esterification reaction under the action of a first catalyst to obtain methyl p-hydroxyphenylpropionate, then mixing the methyl p-hydroxyphenylpropionate with epichlorohydrin, reacting under the action of a second catalyst to obtain 3- [4- (2, 3-epoxypropoxy) phenyl ] methyl propionate, then in a methanol solvent, and sequentially adding the methyl 3- [4- (2, 3-epoxypropoxy) phenyl ] propionate, isopropylamine and hydrogen chloride, reacting to obtain crude esmolol hydrochloride, and finally sequentially performing heating dissolution, activated carbon decoloration, cooling crystallization, centrifugation and drying on the crude esmolol hydrochloride to obtain the final high-purity esmolol hydrochloride with total impurity content of less than 0.5% and single unknown impurity content of less than 0.05%.)

1. A preparation process of high-purity esmolol hydrochloride is characterized by sequentially comprising the following steps:

s1, carrying out esterification reaction on p-hydroxy phenyl propionic acid and methanol under the action of a first catalyst to obtain methyl p-hydroxy phenyl propionate;

s2, reacting the methyl p-hydroxyphenylpropionate with epichlorohydrin under the action of a second catalyst to obtain methyl 3- [4- (2, 3-epoxypropoxy) phenyl ] propionate;

s3, sequentially adding the methyl 3- [4- (2, 3-epoxypropoxy) phenyl ] propionate, isopropylamine and hydrogen chloride into a methanol solvent, and reacting to obtain crude esmolol hydrochloride;

s4, sequentially carrying out heating dissolution, activated carbon decoloration, cooling crystallization, centrifugation and drying on the crude esmolol hydrochloride to obtain the final high-purity esmolol hydrochloride.

2. The process for preparing highly pure esmolol hydrochloride according to claim 1, wherein the process comprises the following steps: in S1, the first catalyst is concentrated sulfuric acid, the reaction time is 6-7h, and the weight ratio of the concentrated sulfuric acid to the p-hydroxyphenylpropionic acid is (0.005-0.01): 1.

3. the process according to claim 1, wherein in S1, the method for purifying methyl paraben in the esterification reaction product system comprises the following steps: excess solid sodium carbonate is added to the product system for neutralizing sulfuric acid, the weight ratio of sodium carbonate to p-hydroxyphenylpropionic acid being (0.02-0.03): and 1, distilling to remove excessive methanol, adding toluene and purified water for extracting an organic phase, and finally distilling the organic phase for removing the toluene to obtain the purified methyl p-hydroxyphenylpropionate.

4. The process for preparing highly pure esmolol hydrochloride according to claim 1, wherein the process comprises the following steps: in S2, the second catalyst is potassium carbonate.

5. The process for preparing highly pure esmolol hydrochloride according to claim 1, wherein the process comprises the following steps: in S3, esmolol free base is generated in the reaction system as an intermediate before the hydrogen chloride is added, vacuum distillation is needed to remove the remaining methanol and isopropylamine, the temperature of the vacuum distillation operation is 35-40 ℃, the vacuum distillation operation is carried out until the weight of the product in the reaction system is 1.6-1.7 times of the weight of the methyl 3- [4- (2, 3-epoxypropoxy) phenyl ] propionate, the vacuum distillation operation is stopped, and then the hydrogen chloride is introduced.

6. The process according to claim 5, wherein the step of preparing esmolol hydrochloride comprises the following steps: in S3, the pH range of the system is controlled to be 4.0-5.0 in the process of reacting the free base of esmolol with the hydrogen chloride to form salt.

7. The process for preparing highly pure esmolol hydrochloride according to claim 1, wherein the process comprises the following steps: in S4, the heating and dissolving operation temperature is 45-50 ℃, the dissolving solvent is any one of acetone, a mixture of methanol and ethyl acetate, a mixture of acetonitrile and ethyl acetate, and a mixture of ethanol and ethyl acetate, and the weight ratio of the dissolving solvent to the crude esmolol hydrochloride is (2-3): 1.

8. The process according to claim 7, wherein the step of preparing esmolol hydrochloride comprises the following steps: in S4, the weight ratio of methanol to ethyl acetate, the weight ratio of acetonitrile to ethyl acetate, and the weight ratio of ethanol to ethyl acetate are (0.4-0.5): 1.

9. The process for preparing highly pure esmolol hydrochloride according to claim 1, wherein the process comprises the following steps: in S4, in the decoloring operation of the activated carbon, the weight ratio of the activated carbon to the crude esmolol hydrochloride is (0.05-0.1): 1, stirring and decoloring for 15-30 min.

10. The process for preparing highly pure esmolol hydrochloride according to claim 1, wherein the process comprises the following steps: in S4, in the cooling crystallization operation, the cooling crystallization temperature is 10-15 ℃, the crystallization time is 5-6h, and the stirring speed during crystallization is 20-25 r/min; the drying operation mode is vacuum drying, the vacuum pressure is-0.1 to-0.09 MPa, the temperature is 15 to 20 ℃, and the drying time is 10 to 12 hours.

Technical Field

The invention belongs to the technical field of organic chemistry and pharmaceutical chemistry, and particularly relates to a preparation process of high-purity esmolol hydrochloride.

Background

Esmolol hydrochloride is white or white-like crystalline powder, has a chemical name of 3- [4- [ 2-hydroxy-3- (isopropylamino) propoxy ] -phenyl ] methyl propionate hydrochloride, can be used as an ultrashort-acting beta-receptor blocker with heart selectivity, has the action characteristics of quick response, short action time (the half-life period is only 9.2 min) and selective blocking of a beta 1-receptor, and is mainly used for treating cardiovascular diseases clinically.

According to the USP requirement, the content of single unknown single impurity is less than 0.1 percent and the total impurity is less than 1.0 percent except the known impurities (acid degradation product RRT0.43 is less than or equal to 0.4 percent, isopropamide compound RRT0.65 is less than or equal to 0.25 percent, N-ethyl compound RRT0.84 is less than or equal to 0.15 percent and dimer RRT6.5 is less than or equal to 0.5 percent) in esmolol hydrochloride need to meet the requirement.

The preparation and refining methods of esmolol hydrochloride are reported, the purification is realized by mainly heating and dissolving ethyl acetate and then cooling and crystallizing, and the liquid-solid ratio of single refining is more than 15. Although the unknown single impurity is reduced after multiple refining, the single unknown single impurity is still higher than 0.05 percent, and the problems of reduced yield, increased cost and large environmental protection load are caused.

Therefore, in view of the above, there is an urgent need for an improved esmolol hydrochloride preparation process to ensure that the total impurity of the finally obtained esmolol hydrochloride product is less than 0.5%, and the single unknown impurity is less than 0.05%.

Chinese patent publication No. CN101891636A, published as 2020.11.24, discloses a novel method for preparing esmolol hydrochloride optical isomers, comprising adding alkali into methyl p-hydroxyphenylpropionate in an anhydrous aprotic polar solvent to prepare phenolate, condensing with (S) -glycidyl derivative or (R) -glycidyl derivative to prepare an intermediate, aminolyzing with isopropylamine, salifying with hydrogen chloride to obtain the optically active esmolol hydrochloride, and refining to obtain pure (S) -esmolol hydrochloride or (R) -esmolol hydrochloride.

However, the esmolol hydrochloride preparation method disclosed by the invention has poor refining effect, and the final total impurity content is less than 0.5%, so that the final esmolol hydrochloride product has the problem of relatively poor total impurity index.

Disclosure of Invention

The invention aims to provide a preparation process of high-purity esmolol hydrochloride, which comprises the steps of firstly mixing p-hydroxyphenylpropionic acid and methanol, carrying out esterification reaction under the action of a first catalyst to obtain methyl p-hydroxyphenylpropionate, then mixing the methyl p-hydroxyphenylpropionate with epichlorohydrin, reacting under the action of a second catalyst to obtain 3- [4- (2, 3-epoxypropoxy) phenyl ] methyl propionate, then in a methanol solvent, and sequentially adding the methyl 3- [4- (2, 3-epoxypropoxy) phenyl ] propionate, isopropylamine and hydrogen chloride, reacting to obtain crude esmolol hydrochloride, and finally sequentially performing heating dissolution, activated carbon decoloration, cooling crystallization, centrifugation and drying on the crude esmolol hydrochloride to obtain the final high-purity esmolol hydrochloride with total impurity content of less than 0.5% and single unknown impurity content of less than 0.05%.

The technical scheme adopted by the invention for solving the problems is as follows: a preparation process of high-purity esmolol hydrochloride sequentially comprises the following steps:

s1, carrying out esterification reaction on p-hydroxy phenyl propionic acid and methanol under the action of a first catalyst to obtain methyl p-hydroxy phenyl propionate;

s2, reacting the methyl p-hydroxyphenylpropionate with epichlorohydrin under the action of a second catalyst to obtain methyl 3- [4- (2, 3-epoxypropoxy) phenyl ] propionate;

s3, sequentially adding the methyl 3- [4- (2, 3-epoxypropoxy) phenyl ] propionate, isopropylamine and hydrogen chloride into a methanol solvent, and reacting to obtain crude esmolol hydrochloride;

s4, sequentially carrying out heating dissolution, activated carbon decoloration, cooling crystallization, centrifugation and drying on the crude esmolol hydrochloride to obtain the final high-purity esmolol hydrochloride.

In the invention, the structural formula of the esmolol hydrochloride is as follows:

。

the further preferred technical scheme is as follows: in S1, the first catalyst is concentrated sulfuric acid, the reaction time is 6-7h, and the weight ratio of the concentrated sulfuric acid to the p-hydroxyphenylpropionic acid is (0.005-0.01): 1.

in the present invention, the reaction formula of S1 is:

。

in S1, the method for purifying methyl p-hydroxyphenylpropionate in the product system of the esterification reaction sequentially comprises: excess solid sodium carbonate is added to the product system for neutralizing sulfuric acid, the weight ratio of sodium carbonate to p-hydroxyphenylpropionic acid being (0.02-0.03): and 1, distilling to remove excessive methanol, adding toluene and purified water for extracting an organic phase, and finally distilling the organic phase for removing the toluene to obtain the purified methyl p-hydroxyphenylpropionate.

In the invention, the final purity of the methyl p-hydroxyphenylpropionate can reach more than 99 percent, and the yield can reach 95 percent.

The further preferred technical scheme is as follows: in S2, the second catalyst is potassium carbonate.

In the present invention, the reaction formula of S2 is:

。

the further preferred technical scheme is as follows: in S3, esmolol free base is generated in the reaction system as an intermediate before the hydrogen chloride is added, vacuum distillation is needed to remove the remaining methanol and isopropylamine, the temperature of the vacuum distillation operation is 35-40 ℃, the vacuum distillation operation is carried out until the weight of the product in the reaction system is 1.6-1.7 times of the weight of the methyl 3- [4- (2, 3-epoxypropoxy) phenyl ] propionate, the vacuum distillation operation is stopped, and then the hydrogen chloride is introduced.

In the present invention, the reaction formula of S3 is:

。

the further preferred technical scheme is as follows: in S3, the pH range of the system is controlled to be 4.0-5.0 in the process of reacting the free base of esmolol with the hydrogen chloride to form salt.

The further preferred technical scheme is as follows: in S4, the heating and dissolving operation temperature is 45-50 ℃, the dissolving solvent is any one of acetone, a mixture of methanol and ethyl acetate, a mixture of acetonitrile and ethyl acetate, and a mixture of ethanol and ethyl acetate, and the weight ratio of the dissolving solvent to the crude esmolol hydrochloride is (2-3): 1.

The further preferred technical scheme is as follows: in S4, the weight ratio of methanol to ethyl acetate, the weight ratio of acetonitrile to ethyl acetate, and the weight ratio of ethanol to ethyl acetate are (0.4-0.5): 1.

The further preferred technical scheme is as follows: in S4, in the decoloring operation of the activated carbon, the weight ratio of the activated carbon to the crude esmolol hydrochloride is (0.05-0.1): 1, stirring and decoloring for 15-30 min.

The further preferred technical scheme is as follows: in S4, in the cooling crystallization operation, the cooling crystallization temperature is 10-15 ℃, the crystallization time is 5-6h, and the stirring speed during crystallization is 20-25 r/min; the drying operation mode is vacuum drying, the vacuum pressure is-0.1 to-0.09 MPa, and the temperature is 15 to 20 ℃. The drying time is 10-12 h.

The invention has the following advantages: firstly, before the intermediate methyl p-hydroxyphenylpropionate is used for removing methanol by evaporation, solid sodium carbonate is added to neutralize sulfuric acid, so that the reverse reaction in the methanol evaporation process is reduced, water for purification is reduced, the yield is increased from 80% to 95%, the cost is greatly reduced, and a foundation is laid for ensuring the subsequent total yield; secondly, controlling the weight of the final distillation residue and the pH value of a salification end point in the process of distilling off methanol and isopropylamine after the completion of the reaction of the intermediate esmolol, and reducing the generation of unknown single impurities of RRT at 3.55 and 5.85; thirdly, solvents with stronger polarity such as acetone and the like are adopted for refining the crude product, so that better results are obtained under the idea of taking yield and quality into consideration, the usage amount of the solvents is reduced, the cost is greatly reduced, and simultaneously, the effects that the single unknown single impurity is lower than 0.05 percent and the total impurity is lower than 0.5 percent are realized.

Drawings

FIG. 1 is an HPLC chromatogram of crude esmolol hydrochloride prepared in example 1 of the present invention.

FIG. 2 is an HPLC chromatogram of the finished high-purity esmolol hydrochloride of example 1 in the present invention.

FIG. 3 is an HPLC chromatogram of the high purity esmolol hydrochloride product of example 2 in the present invention.

FIG. 4 is an HPLC chromatogram of the finished high-purity esmolol hydrochloride product of example 3 in the present invention.

FIG. 5 is an HPLC chromatogram of the high purity esmolol hydrochloride product of example 4 in the present invention.

Detailed Description

The following description is only a preferred embodiment of the present invention and is not intended to limit the scope of the present invention.

Example 1

Firstly, preparing methyl p-hydroxyphenylpropionate:

150g of p-hydroxyphenylacetic acid, 400g of anhydrous methanol and 0.2ml of concentrated sulfuric acid, heating and refluxing for 6 hours, adding 3.0g of sodium carbonate to neutralize sulfuric acid after the reaction is finished, then evaporating the methanol under reduced pressure, adding 400g of toluene, extracting and layering 500g of purified water to obtain an organic phase, and concentrating the organic phase under reduced pressure to obtain 154.4g of methyl p-hydroxyphenylpropionate, wherein the purity is 99.0% by HPLC (high performance liquid chromatography) detection, and the yield is 95.3%.

Preparation of methyl di, 3- [4- (2, 3-epoxypropoxy) phenyl ] propionate:

154g of methyl p-hydroxyphenylpropionate, 308g of acetone and 924g of epichlorohydrin, heating to 50 ℃, reacting for 40 hours, then carrying out suction filtration, carrying out reduced pressure distillation on the filtrate, and concentrating to obtain 140g of methyl 3- [4- [ 2-hydroxy-3- (isopropylamino) propoxy ] -phenyl ] propionate, wherein the purity is 90.1% by HPLC (high performance liquid chromatography) detection, and the yield is 69.4%.

Thirdly, preparing esmolol hydrochloride (crude product):

136g of methyl 3- [4- [ 2-hydroxy-3- (isopropylamino) propoxy ] -phenyl ] propionate, 326g of methanol and 136g of isopropylamine, and the temperature is raised to 40 ℃ for reaction for 4 hours. And after the reaction is finished, carrying out reduced pressure distillation at the temperature until the weight of the concentrated solution reaches 230g, adding 680g of ethyl acetate, adjusting the pH value to 4.6 by using hydrogen chloride, carrying out crystallization for 15 minutes, carrying out suction filtration to obtain a crude esmolol hydrochloride product, putting the coarse esmolol hydrochloride product into an oven, carrying out forced air drying at room temperature to obtain 100.4g, and carrying out HPLC detection to obtain the purity of 99.19% and the yield of 52.7%.

Fourthly, refining a crude product:

20g of esmolol hydrochloride crude product and 60g of acetone, heating to 50 ℃ for dissolving and transparent, adding 1g of activated carbon, stirring for 30 minutes, performing suction filtration, and collecting filtrate. Cooling the filtrate to 10 ℃ for crystallization for 6 hours, controlling the stirring speed to be 20 r/min, performing suction filtration, putting the filter cake into an oven, controlling the temperature to be 15 ℃ and the vacuum pressure to be-0.09 MPa, and drying for 10 hours to obtain 15.7g of esmolol hydrochloride finished product with the yield of 78.5%. Purity 99.71% by HPLC, single unknown impurity less than 0.05%, other known impurities meet USP requirements.

Example 2

20g of the crude product prepared in example 1, 16g of methanol and 40g of ethyl acetate are heated to 50 ℃ to be dissolved and transparent, 1.5g of activated carbon is added, the mixture is stirred for 20 minutes, and the filtrate is collected after suction filtration. Cooling the filtrate to 15 ℃ for crystallization for 6 hours, controlling the stirring speed to 25r/min, performing suction filtration, putting the filter cake into an oven, controlling the temperature to be 20 ℃ and the vacuum pressure to be-0.1 MPa, and drying for 12 hours to obtain 14.5g of esmolol hydrochloride finished product with the yield of 70.3%. Purity by HPLC was 99.73%, single unknown impurity was less than 0.05%, other known impurities met USP requirements.

Example 3

20g of the crude product prepared in the example 1, 20g of ethanol and 20g of ethyl acetate are heated to 45 ℃ to be dissolved and transparent, 2g of activated carbon is added, the mixture is stirred for 20 minutes, and the filtrate is collected after suction filtration. Cooling the filtrate to 10 ℃ for crystallization for 5 hours, controlling the stirring speed to 25r/min, performing suction filtration, putting the filter cake into an oven, controlling the temperature to be 20 ℃ and the vacuum pressure to be-0.09 MPa, and drying for 10 hours to obtain a finished product of esmolol hydrochloride, namely 16.5g, wherein the yield is 82.5%. Purity 99.74% by HPLC, single unknown impurity less than 0.05%, other known impurities meeting USP requirements.

Example 4

20g of the crude product prepared in example 1, 20g of acetonitrile and 40g of ethyl acetate are heated to 50 ℃ to be dissolved and transparent, 1.5g of activated carbon is added, the mixture is stirred for 30 minutes, and the filtrate is collected after suction filtration. Cooling the filtrate to 15 ℃ for crystallization for 6 hours, controlling the stirring speed to be 20 r/min, performing suction filtration, putting the filter cake into an oven, controlling the temperature to be 20 ℃ and the vacuum pressure to be-0.09 MPa, and drying for 12 hours to obtain 14.8g of the finished product of esmolol hydrochloride with the yield of 74.0%. Purity by HPLC was 99.73%, single unknown impurity was less than 0.05%, other known impurities met USP requirements.

The embodiments of the present invention have been described in detail with reference to the accompanying drawings, but the present invention is not limited to the above embodiments, and various modifications can be made within the knowledge of those skilled in the art without departing from the gist of the present invention. These are non-inventive modifications, which are intended to be protected by patent laws within the scope of the claims appended hereto.